The shape and size of organs is controlled by the position, number, and size of its cells which in turn depend on cell proliferation, cell migration, and cell death. An interesting point in case is somitogenesis which in different axial levels proceeds along stereotypic pathways but leads to structures of distinct size and shape. We have analyzed a line of transgenic mice with a recessive insertional mutation that is characterized by region-specific alterations in the axial skeleton, particularly in the area of the cranio-cervical joint. These mice also have a severe deficiency in lactation. Intriguingly, each of these phenotypes has its corresponding counterpart in mice with mutations in proteins known or thought to be involved in the regulation of cell proliferation. We found that the insertion has created a loss-of-function mutation in the gene encoding the Meox1 homeodomain transcription factor. This factor is related to the homeodomain protein Meox2, also known as Gax, whose overexpression leads to growth arrest of a variety of cultured cells. To test for genetic interactions between Meox1 and Meox2, we have, in collaborative efforts, analyzed Meox1 and Meox2 expression in Meox1 and Meox2 mutant mice and found that mutations in one gene do not lead to striking effects on the expression of the other. While mice homozygous for either of the single mutations live at least to weaning, Meox1/Meox2 double mutants are stillborn, display a rudimentary axial skeleton, fused dorsal root ganglia, unevenly spaced motor axons, and lack ribs. These alterations result from malformations in the somites which are irregularly sized, shaped, and spaced and lack the cellular condensations that normally occur in the caudal parts of the sclerotome. Thus, Meox1 and Meox2 act in concert to bring about the normal development of the sclerotome, but how they exert their function is not clear at present. In particular, it is unknown whether Meox1 or Meox2 reduce cell proliferation in vivo and how a loss of function in these proteins would lead to deletions of particular structures. Our studies have the final goal to elucidate the underlying molecular and cell biological mechanisms and to test whether humans with similar pathology may have mutations in the homologous genes.